Merck Announces KEYNOTE-598 Trial Evaluating
KEYTRUDA® (pembrolizumab) in Combination With Ipilimumab Versus
KEYTRUDA Monotherapy in Certain Patients With Metastatic Non-Small
Cell Lung Cancer To Stop for Futility and Patients to Discontinue
Ipilimumab
Merck (NYSE: MRK), known as MSD outside the United States and
Canada, today announced that it will be stopping KEYNOTE-598, a
Phase 3 trial investigating KEYTRUDA, Merck’s anti-PD-1 therapy, in
combination with ipilimumab (Yervoy®), compared with KEYTRUDA
monotherapy, for the first-line treatment of patients with
metastatic non-small cell lung cancer (NSCLC) whose tumors express
PD-L1 (tumor proportion score [TPS] ≥50%) with no EGFR or ALK
genomic tumor aberrations. Merck is discontinuing the study
following the recommendation of an independent Data Monitoring
Committee (DMC), which determined the benefit/risk profile of the
combination did not support continuing the trial. At an interim
analysis, the combination of KEYTRUDA and ipilimumab showed no
incremental benefit in overall survival (OS) or progression-free
survival (PFS), the study’s dual primary endpoints, compared with
KEYTRUDA alone and crossed futility boundaries. No new safety
signals for KEYTRUDA monotherapy were observed, however the
combination of KEYTRUDA and ipilimumab was associated with a higher
incidence of grade 3-5 adverse events (AEs), serious AEs, and AEs
leading to discontinuation or death, compared with KEYTRUDA
monotherapy. Merck will inform study investigators of the
recommendation from the DMC and the DMC is advising that patients
in the study discontinue treatment with ipilimumab/placebo. Data
from this study will be submitted for presentation at an upcoming
scientific congress and communicated to regulatory agencies.
“We conducted KEYNOTE-598 in order to explicitly explore whether
combining our anti-PD-1 therapy, KEYTRUDA, with ipilimumab provided
additional benefits beyond treatment with KEYTRUDA alone in the
metastatic non-small cell lung cancer setting,” said Dr. Roy
Baynes, senior vice president and head of global clinical
development, chief medical officer, Merck Research Laboratories.
“It is very clear that in this study, the addition of ipilimumab
did not add clinical benefit but did add toxicity. KEYTRUDA
monotherapy remains a standard of care for the treatment of certain
patients with metastatic non-small cell lung cancer whose tumors
express PD-L1.”
While the combination of an anti-PD-1 therapy plus ipilimumab
has been approved in certain indications, studies supporting these
approvals have, for the most part, not compared the combination
directly with anti-PD-1 monotherapy. Bristol Myers Squibb has
reported topline results of CheckMate-915, a Phase 3 study in
adjuvant melanoma that directly compared treatment with ipilimumab
in combination with an anti-PD-1 therapy versus the anti-PD-1
therapy alone. In two separate news releases issued over the last
year, the company announced the study did not meet its co-primary
endpoints in the all-comer population or in patients whose tumors
expressed PD-L1 <1%. These data have not yet been presented.
Merck has an extensive clinical development program in lung
cancer and is advancing multiple registration-enabling studies with
KEYTRUDA in combination with other treatments and as monotherapy.
The lung program is evaluating KEYTRUDA across all stages of
disease and lines of therapy in over 200 trials with more than
10,000 patients.
About KEYNOTE-598
KEYNOTE-598 (ClinicalTrials.gov, NCT03302234) is a randomized,
double-blind, Phase 3 trial investigating KEYTRUDA in combination
with ipilimumab compared to KEYTRUDA monotherapy for the first-line
treatment of patients with metastatic NSCLC whose tumors express
PD‑L1 (TPS ≥50%) with no EGFR or ALK genomic tumor aberrations. The
dual primary endpoints are OS and PFS. Secondary endpoints include
objective response rate, duration of response and safety. The study
enrolled 568 patients who were randomized (1:1) to receive:
- KEYTRUDA (200 mg intravenously [IV] on Day 1 of each three-week
cycle for up to 35 cycles) in combination with ipilimumab (1 mg/kg
IV on Day 1 of each six-week cycle for up to 18 cycles); or
- KEYTRUDA (200 mg IV on Day 1 of each three-week cycle for up to
35 cycles) in combination with placebo (IV on Day 1 of each
six-week cycle for up to 18 cycles).
About Lung Cancer
Lung cancer, which forms in the tissues of the lungs, usually
within cells lining the air passages, is the leading cause of
cancer death worldwide. Each year, more people die of lung cancer
than die of colon and breast cancers combined. The two main types
of lung cancer are non-small cell and small cell. Non-small cell
lung cancer (NSCLC) is the most common type of lung cancer,
accounting for about 85% of all cases. Small cell lung cancer
(SCLC) accounts for about 10% to 15% of all lung cancers. Before
2014, the five-year survival rate for patients diagnosed in the
U.S. with NSCLC and SCLC was estimated to be 5% and 6%,
respectively.
About KEYTRUDA® (pembrolizumab) Injection, 100 mg
KEYTRUDA is an anti-PD-1 therapy that works by increasing the
ability of the body’s immune system to help detect and fight tumor
cells. KEYTRUDA is a humanized monoclonal antibody that blocks the
interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby
activating T lymphocytes which may affect both tumor cells and
healthy cells.
Merck has the industry’s largest immuno-oncology clinical
research program. There are currently more than 1,200 trials
studying KEYTRUDA across a wide variety of cancers and treatment
settings. The KEYTRUDA clinical program seeks to understand the
role of KEYTRUDA across cancers and the factors that may predict a
patient's likelihood of benefitting from treatment with KEYTRUDA,
including exploring several different biomarkers.
Selected KEYTRUDA® (pembrolizumab) Indications
Melanoma
KEYTRUDA is indicated for the treatment of patients with
unresectable or metastatic melanoma.
KEYTRUDA is indicated for the adjuvant treatment of patients
with melanoma with involvement of lymph node(s) following complete
resection.
Non-Small Cell Lung Cancer
KEYTRUDA, in combination with pemetrexed and platinum
chemotherapy, is indicated for the first-line treatment of patients
with metastatic nonsquamous non-small cell lung cancer (NSCLC),
with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, in combination with carboplatin and either paclitaxel
or paclitaxel protein-bound, is indicated for the first-line
treatment of patients with metastatic squamous NSCLC.
KEYTRUDA, as a single agent, is indicated for the first-line
treatment of patients with NSCLC expressing PD-L1 [tumor proportion
score (TPS) ≥1%] as determined by an FDA-approved test, with no
EGFR or ALK genomic tumor aberrations, and is stage III where
patients are not candidates for surgical resection or definitive
chemoradiation, or metastatic.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%)
as determined by an FDA-approved test, with disease progression on
or after platinum-containing chemotherapy. Patients with EGFR or
ALK genomic tumor aberrations should have disease progression on
FDA-approved therapy for these aberrations prior to receiving
KEYTRUDA.
Small Cell Lung Cancer
KEYTRUDA is indicated for the treatment of patients with
metastatic small cell lung cancer (SCLC) with disease progression
on or after platinum-based chemotherapy and at least 1 other prior
line of therapy. This indication is approved under accelerated
approval based on tumor response rate and durability of response.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in confirmatory
trials.
Head and Neck Squamous Cell Cancer
KEYTRUDA, in combination with platinum and fluorouracil (FU), is
indicated for the first-line treatment of patients with metastatic
or with unresectable, recurrent head and neck squamous cell
carcinoma (HNSCC).
KEYTRUDA, as a single agent, is indicated for the first-line
treatment of patients with metastatic or with unresectable,
recurrent HNSCC whose tumors express PD-L1 [combined positive score
(CPS) ≥1] as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with recurrent or metastatic head and neck squamous cell
carcinoma (HNSCC) with disease progression on or after
platinum-containing chemotherapy.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult patients with
relapsed or refractory classical Hodgkin lymphoma (cHL).
KEYTRUDA is indicated for the treatment of pediatric patients
with refractory cHL, or cHL that has relapsed after 2 or more lines
of therapy.
Primary Mediastinal Large B-Cell Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with refractory primary mediastinal large B-cell lymphoma
(PMBCL), or who have relapsed after 2 or more prior lines of
therapy. KEYTRUDA is not recommended for treatment of patients with
PMBCL who require urgent cytoreductive therapy.
Urothelial Carcinoma
KEYTRUDA is indicated for the treatment of patients with locally
advanced or metastatic urothelial carcinoma (mUC) who are not
eligible for cisplatin-containing chemotherapy and whose tumors
express PD-L1 [combined positive score (CPS) ≥10], as determined by
an FDA-approved test, or in patients who are not eligible for any
platinum-containing chemotherapy regardless of PD-L1 status. This
indication is approved under accelerated approval based on tumor
response rate and duration of response. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in confirmatory trials.
KEYTRUDA is indicated for the treatment of patients with locally
advanced or metastatic urothelial carcinoma (mUC) who have disease
progression during or following platinum-containing chemotherapy or
within 12 months of neoadjuvant or adjuvant treatment with
platinum-containing chemotherapy.
KEYTRUDA is indicated for the treatment of patients with
Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle
invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with
or without papillary tumors who are ineligible for or have elected
not to undergo cystectomy.
Microsatellite Instability-High or Mismatch Repair Deficient
Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with unresectable or metastatic microsatellite
instability-high (MSI-H) or mismatch repair deficient (dMMR)
- solid tumors that have progressed following prior treatment and
who have no satisfactory alternative treatment options, or
- colorectal cancer that has progressed following treatment with
fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on
tumor response rate and durability of response. Continued approval
for this indication may be contingent upon verification and
description of clinical benefit in the confirmatory trials. The
safety and effectiveness of KEYTRUDA in pediatric patients with
MSI-H central nervous system cancers have not been established.
Microsatellite Instability-High or Mismatch Repair Deficient
Colorectal Cancer
KEYTRUDA is indicated for the first-line treatment of patients
with unresectable or metastatic MSI-H or dMMR colorectal cancer
(CRC).
Gastric Cancer
KEYTRUDA is indicated for the treatment of patients with
recurrent locally advanced or metastatic gastric or
gastroesophageal junction (GEJ) adenocarcinoma whose tumors express
PD-L1 (CPS ≥1) as determined by an FDA-approved test, with disease
progression on or after two or more prior lines of therapy
including fluoropyrimidine- and platinum-containing chemotherapy
and if appropriate, HER2/neu-targeted therapy. This indication is
approved under accelerated approval based on tumor response rate
and durability of response. Continued approval for this indication
may be contingent upon verification and description of clinical
benefit in the confirmatory trials.
Esophageal Cancer
KEYTRUDA is indicated for the treatment of patients with
recurrent locally advanced or metastatic squamous cell carcinoma of
the esophagus whose tumors express PD-L1 (CPS ≥10) as determined by
an FDA-approved test, with disease progression after one or more
prior lines of systemic therapy.
Cervical Cancer
KEYTRUDA is indicated for the treatment of patients with
recurrent or metastatic cervical cancer with disease progression on
or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as
determined by an FDA-approved test. This indication is approved
under accelerated approval based on tumor response rate and
durability of response. Continued approval for this indication may
be contingent upon verification and description of clinical benefit
in the confirmatory trials.
Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with
hepatocellular carcinoma (HCC) who have been previously treated
with sorafenib. This indication is approved under accelerated
approval based on tumor response rate and durability of response.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in the
confirmatory trials.
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with recurrent locally advanced or metastatic Merkel cell
carcinoma (MCC). This indication is approved under accelerated
approval based on tumor response rate and durability of response.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in the
confirmatory trials.
Renal Cell Carcinoma
KEYTRUDA, in combination with axitinib, is indicated for the
first-line treatment of patients with advanced renal cell carcinoma
(RCC).
Tumor Mutational Burden-High
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with unresectable or metastatic tumor mutational
burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors,
as determined by an FDA-approved test, that have progressed
following prior treatment and who have no satisfactory alternative
treatment options. This indication is approved under accelerated
approval based on tumor response rate and durability of response.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in the
confirmatory trials. The safety and effectiveness of KEYTRUDA in
pediatric patients with TMB-H central nervous system cancers have
not been established.
Cutaneous Squamous Cell Carcinoma
KEYTRUDA is indicated for the treatment of patients with
recurrent or metastatic cutaneous squamous cell carcinoma (cSCC)
that is not curable by surgery or radiation.
Selected Important Safety Information for KEYTRUDA
Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis, including fatal
cases. Pneumonitis occurred in 3.4% (94/2799) of patients with
various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2
(1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in
8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single
agent, including Grades 3-4 in 3.2% of patients, and occurred more
frequently in patients with a history of prior thoracic radiation
(17%) compared to those without (7.7%). Pneumonitis occurred in 6%
(18/300) of HNSCC patients receiving KEYTRUDA as a single agent,
including Grades 3-5 in 1.6% of patients, and occurred in 5.4%
(15/276) of patients receiving KEYTRUDA in combination with
platinum and FU as first-line therapy for advanced disease,
including Grades 3-5 in 1.5% of patients. Pneumonitis occurred in
8% (31/389) of patients with cHL receiving KEYTRUDA as a single
agent, including Grades 3-4 in 2.3% of patients.
Monitor patients for signs and symptoms of pneumonitis. Evaluate
suspected pneumonitis with radiographic imaging. Administer
corticosteroids for Grade 2 or greater pneumonitis. Withhold
KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3
or 4 or recurrent Grade 2 pneumonitis.
Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis. Colitis occurred in
1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2
(0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and
symptoms of colitis. Administer corticosteroids for Grade 2 or
greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently
discontinue KEYTRUDA for Grade 4 colitis.
Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity
(KEYTRUDA in Combination With Axitinib)
Immune-Mediated Hepatitis
KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred
in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2
(0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in
liver function. Administer corticosteroids for Grade 2 or greater
hepatitis and, based on severity of liver enzyme elevations,
withhold or discontinue KEYTRUDA.
Hepatotoxicity in Combination With Axitinib
KEYTRUDA in combination with axitinib can cause hepatic toxicity
with higher than expected frequencies of Grades 3 and 4 ALT and AST
elevations compared to KEYTRUDA alone. With the combination of
KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and
increased AST (13%) were seen. Monitor liver enzymes before
initiation of and periodically throughout treatment. Consider more
frequent monitoring of liver enzymes as compared to when the drugs
are administered as single agents. For elevated liver enzymes,
interrupt KEYTRUDA and axitinib, and consider administering
corticosteroids as needed.
Immune-Mediated Endocrinopathies
KEYTRUDA can cause adrenal insufficiency (primary and
secondary), hypophysitis, thyroid disorders, and type 1 diabetes
mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of
patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%).
Hypophysitis occurred in 0.6% (17/2799) of patients, including
Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred
in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3
(0.1%). The incidence of new or worsening hypothyroidism was higher
in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single
agent or in combination with platinum and FU, including Grade 3
(0.3%) hypothyroidism. The incidence of new or worsening
hypothyroidism was higher in 389 patients with cHL (17%) receiving
KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2
(10.8%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799)
of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis
occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%).
Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred
in 0.2% (6/2799) of patients.
Monitor patients for signs and symptoms of adrenal
insufficiency, hypophysitis (including hypopituitarism), thyroid
function (prior to and periodically during treatment), and
hyperglycemia. For adrenal insufficiency or hypophysitis,
administer corticosteroids and hormone replacement as clinically
indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or
hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or
Grade 4 adrenal insufficiency or hypophysitis. Administer hormone
replacement for hypothyroidism and manage hyperthyroidism with
thionamides and beta-blockers as appropriate. Withhold or
discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer
insulin for type 1 diabetes, and withhold KEYTRUDA and administer
antihyperglycemics in patients with severe hyperglycemia.
Immune-Mediated Nephritis and Renal Dysfunction
KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred
in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2
(0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in
1.7% (7/405) of patients receiving KEYTRUDA in combination with
pemetrexed and platinum chemotherapy. Monitor patients for changes
in renal function. Administer corticosteroids for Grade 2 or
greater nephritis. Withhold KEYTRUDA for Grade 2; permanently
discontinue for Grade 3 or 4 nephritis.
Immune-Mediated Skin Reactions
Immune-mediated rashes, including Stevens-Johnson syndrome
(SJS), toxic epidermal necrolysis (TEN) (some cases with fatal
outcome), exfoliative dermatitis, and bullous pemphigoid, can
occur. Monitor patients for suspected severe skin reactions and
based on the severity of the adverse reaction, withhold or
permanently discontinue KEYTRUDA and administer corticosteroids.
For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer
the patient for specialized care for assessment and treatment. If
SJS or TEN is confirmed, permanently discontinue KEYTRUDA.
Other Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions, which may be severe or fatal,
can occur in any organ system or tissue in patients receiving
KEYTRUDA and may also occur after discontinuation of treatment. For
suspected immune-mediated adverse reactions, ensure adequate
evaluation to confirm etiology or exclude other causes. Based on
the severity of the adverse reaction, withhold KEYTRUDA and
administer corticosteroids. Upon improvement to Grade 1 or less,
initiate corticosteroid taper and continue to taper over at least 1
month. Based on limited data from clinical studies in patients
whose immune-related adverse reactions could not be controlled with
corticosteroid use, administration of other systemic
immunosuppressants can be considered. Resume KEYTRUDA when the
adverse reaction remains at Grade 1 or less following
corticosteroid taper. Permanently discontinue KEYTRUDA for any
Grade 3 immune-mediated adverse reaction that recurs and for any
life-threatening immune-mediated adverse reaction.
The following clinically significant immune-mediated adverse
reactions occurred in less than 1% (unless otherwise indicated) of
2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré
syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic
anemia, sarcoidosis, and encephalitis. In addition, myelitis and
myocarditis were reported in other clinical trials, including
classical Hodgkin lymphoma, and post-marketing use.
Treatment with KEYTRUDA may increase the risk of rejection in
solid organ transplant recipients. Consider the benefit of
treatment vs the risk of possible organ rejection in these
patients.
Infusion-Related Reactions
KEYTRUDA can cause severe or life-threatening infusion-related
reactions, including hypersensitivity and anaphylaxis, which have
been reported in 0.2% (6/2799) of patients. Monitor patients for
signs and symptoms of infusion-related reactions. For Grade 3 or 4
reactions, stop infusion and permanently discontinue KEYTRUDA.
Complications of Allogeneic Hematopoietic Stem Cell
Transplantation (HSCT)
Fatal and other serious complications can occur in patients who
receive allogeneic hematopoietic stem cell transplantation (HSCT)
before or after being treated with a PD-1/PD-L1 blocking antibody.
Transplant-related complications include hyperacute
graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic
veno-occlusive disease (VOD) after reduced intensity conditioning,
and steroid-requiring febrile syndrome (without an identified
infectious cause). These complications may occur despite
intervening therapy between PD-1/PD-L1 blockade and allogeneic
HSCT. Follow patients closely for evidence of transplant-related
complications and intervene promptly. Consider the benefit versus
risk of treatment with a PD-1/PD-L1 blocking antibody prior to or
after an allogeneic HSCT.
Increased Mortality in Patients With Multiple Myeloma
In trials in patients with multiple myeloma, the addition of
KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in
increased mortality. Treatment of these patients with a PD-1 or
PD-L1 blocking antibody in this combination is not recommended
outside of controlled trials.
Embryofetal Toxicity
Based on its mechanism of action, KEYTRUDA can cause fetal harm
when administered to a pregnant woman. Advise women of this
potential risk. In females of reproductive potential, verify
pregnancy status prior to initiating KEYTRUDA and advise them to
use effective contraception during treatment and for 4 months after
the last dose.
Adverse Reactions
In KEYNOTE-006, KEYTRUDA was discontinued due to adverse
reactions in 9% of 555 patients with advanced melanoma; adverse
reactions leading to permanent discontinuation in more than one
patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic
reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%).
The most common adverse reactions (≥20%) with KEYTRUDA were fatigue
(28%), diarrhea (26%), rash (24%), and nausea (21%).
In KEYNOTE-002, KEYTRUDA was permanently discontinued due to
adverse reactions in 12% of 357 patients with advanced melanoma;
the most common (≥1%) were general physical health deterioration
(1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and
generalized edema (1%). The most common adverse reactions were
fatigue (43%), pruritus (28%), rash (24%), constipation (22%),
nausea (22%), diarrhea (20%), and decreased appetite (20%).
In KEYNOTE-054, KEYTRUDA was permanently discontinued due to
adverse reactions in 14% of 509 patients; the most common (≥1%)
were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious
adverse reactions occurred in 25% of patients receiving KEYTRUDA.
The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea
(28%).
In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed
and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA
was discontinued due to adverse reactions in 20% of 405 patients.
The most common adverse reactions resulting in permanent
discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney
injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA
were nausea (56%), fatigue (56%), constipation (35%), diarrhea
(31%), decreased appetite (28%), rash (25%), vomiting (24%), cough
(21%), dyspnea (21%), and pyrexia (20%).
In KEYNOTE-407, when KEYTRUDA was administered with carboplatin
and either paclitaxel or paclitaxel protein-bound in metastatic
squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions
in 15% of 101 patients. The most frequent serious adverse reactions
reported in at least 2% of patients were febrile neutropenia,
pneumonia, and urinary tract infection. Adverse reactions observed
in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with
the exception that increased incidences of alopecia (47% vs 36%)
and peripheral neuropathy (31% vs 25%) were observed in the
KEYTRUDA and chemotherapy arm compared to the placebo and
chemotherapy arm in KEYNOTE-407.
In KEYNOTE-042, KEYTRUDA was discontinued due to adverse
reactions in 19% of 636 patients with advanced NSCLC; the most
common were pneumonitis (3%), death due to unknown cause (1.6%),
and pneumonia (1.4%). The most frequent serious adverse reactions
reported in at least 2% of patients were pneumonia (7%),
pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion
(2.2%). The most common adverse reaction (≥20%) was fatigue
(25%).
In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to
adverse reactions in 8% of 682 patients with metastatic NSCLC; the
most common was pneumonitis (1.8%). The most common adverse
reactions (≥20%) were decreased appetite (25%), fatigue (25%),
dyspnea (23%), and nausea (20%).
Adverse reactions occurring in patients with SCLC were similar
to those occurring in patients with other solid tumors who received
KEYTRUDA as a single agent.
In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to
adverse events in 12% of 300 patients with HNSCC; the most common
adverse reactions leading to permanent discontinuation were sepsis
(1.7%) and pneumonia (1.3%). The most common adverse reactions
(≥20%) were fatigue (33%), constipation (20%), and rash (20%).
In KEYNOTE-048, when KEYTRUDA was administered in combination
with platinum (cisplatin or carboplatin) and FU chemotherapy,
KEYTRUDA was discontinued due to adverse reactions in 16% of 276
patients with HNSCC. The most common adverse reactions resulting in
permanent discontinuation of KEYTRUDA were pneumonia (2.5%),
pneumonitis (1.8%), and septic shock (1.4%). The most common
adverse reactions (≥20%) were nausea (51%), fatigue (49%),
constipation (37%), vomiting (32%), mucosal inflammation (31%),
diarrhea (29%), decreased appetite (29%), stomatitis (26%), and
cough (22%).
In KEYNOTE-012, KEYTRUDA was discontinued due to adverse
reactions in 17% of 192 patients with HNSCC. Serious adverse
reactions occurred in 45% of patients. The most frequent serious
adverse reactions reported in at least 2% of patients were
pneumonia, dyspnea, confusional state, vomiting, pleural effusion,
and respiratory failure. The most common adverse reactions (≥20%)
were fatigue, decreased appetite, and dyspnea. Adverse reactions
occurring in patients with HNSCC were generally similar to those
occurring in patients with melanoma or NSCLC who received KEYTRUDA
as a monotherapy, with the exception of increased incidences of
facial edema and new or worsening hypothyroidism.
In KEYNOTE-204, KEYTRUDA was discontinued due to adverse
reactions in 14% of 148 patients with cHL. Serious adverse
reactions occurred in 30% of patients; those ≥1% included
pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury,
febrile neutropenia, and sepsis. Three patients died from causes
other than disease progression. The most common adverse reactions
(≥20%) were upper respiratory tract infection (41%),
musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue,
and cough (20% each).
In KEYNOTE-087, KEYTRUDA was discontinued due to adverse
reactions in 5% of 210 patients with cHL. Serious adverse reactions
occurred in 16% of patients; those ≥1% included pneumonia,
pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two
patients died from causes other than disease progression; 1 from
GVHD after subsequent allogeneic HSCT and 1 from septic shock. The
most common adverse reactions (≥20%) were fatigue (26%), pyrexia
(24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and
rash (20%).
In KEYNOTE-170, KEYTRUDA was discontinued due to adverse
reactions in 8% of 53 patients with PMBCL. Serious adverse
reactions occurred in 26% of patients and included arrhythmia (4%),
cardiac tamponade (2%), myocardial infarction (2%), pericardial
effusion (2%), and pericarditis (2%). Six (11%) patients died
within 30 days of start of treatment. The most common adverse
reactions (≥20%) were musculoskeletal pain (30%), upper respiratory
tract infection and pyrexia (28% each), cough (26%), fatigue (23%),
and dyspnea (21%).
In KEYNOTE-052, KEYTRUDA was discontinued due to adverse
reactions in 11% of 370 patients with locally advanced or
metastatic urothelial carcinoma. Serious adverse reactions occurred
in 42% of patients; those ≥2% were urinary tract infection,
hematuria, acute kidney injury, pneumonia, and urosepsis. The most
common adverse reactions (≥20%) were fatigue (38%), musculoskeletal
pain (24%), decreased appetite (22%), constipation (21%), rash
(21%), and diarrhea (20%).
In KEYNOTE-045, KEYTRUDA was discontinued due to adverse
reactions in 8% of 266 patients with locally advanced or metastatic
urothelial carcinoma. The most common adverse reaction resulting in
permanent discontinuation of KEYTRUDA was pneumonitis (1.9%).
Serious adverse reactions occurred in 39% of KEYTRUDA-treated
patients; those ≥2% were urinary tract infection, pneumonia,
anemia, and pneumonitis. The most common adverse reactions (≥20%)
in patients who received KEYTRUDA were fatigue (38%),
musculoskeletal pain (32%), pruritus (23%), decreased appetite
(21%), nausea (21%), and rash (20%).
In KEYNOTE-057, KEYTRUDA was discontinued due to adverse
reactions in 11% of 148 patients with high-risk NMIBC. The most
common adverse reaction resulting in permanent discontinuation of
KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred
in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia
(2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and
urinary tract infection (2%). The most common adverse reactions
(≥20%) were fatigue (29%), diarrhea (24%), and rash (24%).
Adverse reactions occurring in patients with MSI-H or dMMR CRC
were similar to those occurring in patients with melanoma or NSCLC
who received KEYTRUDA as a monotherapy.
Adverse reactions occurring in patients with gastric cancer were
similar to those occurring in patients with melanoma or NSCLC who
received KEYTRUDA as a monotherapy.
Adverse reactions occurring in patients with esophageal cancer
were similar to those occurring in patients with melanoma or NSCLC
who received KEYTRUDA as a monotherapy.
In KEYNOTE-158, KEYTRUDA was discontinued due to adverse
reactions in 8% of 98 patients with recurrent or metastatic
cervical cancer. Serious adverse reactions occurred in 39% of
patients receiving KEYTRUDA; the most frequent included anemia
(7%), fistula, hemorrhage, and infections [except urinary tract
infections] (4.1% each). The most common adverse reactions (≥20%)
were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%),
pain and abdominal pain (22% each), and decreased appetite
(21%).
Adverse reactions occurring in patients with hepatocellular
carcinoma (HCC) were generally similar to those in patients with
melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the
exception of increased incidences of ascites (8% Grades 3-4) and
immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades
3-4) that occurred at a higher incidence were elevated AST (20%),
ALT (9%), and hyperbilirubinemia (10%).
Among the 50 patients with MCC enrolled in study KEYNOTE-017,
adverse reactions occurring in patients with MCC were generally
similar to those occurring in patients with melanoma or NSCLC who
received KEYTRUDA as a monotherapy. Laboratory abnormalities
(Grades 3-4) that occurred at a higher incidence were elevated AST
(11%) and hyperglycemia (19%).
In KEYNOTE-426, when KEYTRUDA was administered in combination
with axitinib, fatal adverse reactions occurred in 3.3% of 429
patients. Serious adverse reactions occurred in 40% of patients,
the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%),
acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%).
Permanent discontinuation due to an adverse reaction occurred in
31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the
combination (8%); the most common were hepatotoxicity (13%),
diarrhea/colitis (1.9%), acute kidney injury (1.6%), and
cerebrovascular accident (1.2%). The most common adverse reactions
(≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension
(48%), hepatotoxicity (39%), hypothyroidism (35%), decreased
appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea
(28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash
(25%), cough (21%), and constipation (21%).
Adverse reactions occurring in patients with TMB-H cancer were
similar to those occurring in patients with other solid tumors who
received KEYTRUDA as a single agent.
Adverse reactions occurring in patients with cSCC were similar
to those occurring in patients with melanoma or NSCLC who received
KEYTRUDA as a monotherapy.
Lactation
Because of the potential for serious adverse reactions in
breastfed children, advise women not to breastfeed during treatment
and for 4 months after the final dose.
Pediatric Use
In KEYNOTE-051, 161 pediatric patients (62 pediatric patients
aged 6 months to younger than 12 years and 99 pediatric patients
aged 12 years to 17 years) were administered KEYTRUDA 2 mg/kg every
3 weeks. The median duration of exposure was 2.1 months (range: 1
day to 24 months).
Adverse reactions that occurred at a ≥10% higher rate in
pediatric patients when compared to adults were pyrexia (33%),
vomiting (30%), leukopenia (30%), upper respiratory tract infection
(29%), neutropenia (26%), headache (25%), and Grade 3 anemia
(17%).
Merck’s Focus on Cancer
Our goal is to translate breakthrough science into innovative
oncology medicines to help people with cancer worldwide. At Merck,
the potential to bring new hope to people with cancer drives our
purpose and supporting accessibility to our cancer medicines is our
commitment. As part of our focus on cancer, Merck is committed to
exploring the potential of immuno-oncology with one of the largest
development programs in the industry across more than 30 tumor
types. We also continue to strengthen our portfolio through
strategic acquisitions and are prioritizing the development of
several promising oncology candidates with the potential to improve
the treatment of advanced cancers. For more information about our
oncology clinical trials, visit www.merck.com/clinicaltrials.
About Merck
For more than 125 years, Merck, known as MSD outside of the
United States and Canada, has been inventing for life, bringing
forward medicines and vaccines for many of the world’s most
challenging diseases in pursuit of our mission to save and improve
lives. We demonstrate our commitment to patients and population
health by increasing access to health care through far-reaching
policies, programs and partnerships. Today, Merck continues to be
at the forefront of research to prevent and treat diseases that
threaten people and animals – including cancer, infectious diseases
such as HIV and Ebola, and emerging animal diseases – as we aspire
to be the premier research-intensive biopharmaceutical company in
the world. For more information, visit www.merck.com and connect
with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.
Forward-Looking Statement of Merck & Co., Inc.,
Kenilworth, N.J., USA
This news release of Merck & Co., Inc., Kenilworth, N.J.,
USA (the “company”) includes “forward-looking statements” within
the meaning of the safe harbor provisions of the U.S. Private
Securities Litigation Reform Act of 1995. These statements are
based upon the current beliefs and expectations of the company’s
management and are subject to significant risks and uncertainties.
There can be no guarantees with respect to pipeline products that
the products will receive the necessary regulatory approvals or
that they will prove to be commercially successful. If underlying
assumptions prove inaccurate or risks or uncertainties materialize,
actual results may differ materially from those set forth in the
forward-looking statements.
Risks and uncertainties include but are not limited to, general
industry conditions and competition; general economic factors,
including interest rate and currency exchange rate fluctuations;
the impact of the global outbreak of novel coronavirus disease
(COVID-19); the impact of pharmaceutical industry regulation and
health care legislation in the United States and internationally;
global trends toward health care cost containment; technological
advances, new products and patents attained by competitors;
challenges inherent in new product development, including obtaining
regulatory approval; the company’s ability to accurately predict
future market conditions; manufacturing difficulties or delays;
financial instability of international economies and sovereign
risk; dependence on the effectiveness of the company’s patents and
other protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory
actions.
The company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause
results to differ materially from those described in the
forward-looking statements can be found in the company’s 2019
Annual Report on Form 10-K and the company’s other filings with the
Securities and Exchange Commission (SEC) available at the SEC’s
Internet site (www.sec.gov).
Please see Prescribing Information for KEYTRUDA at
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
and Medication Guide for KEYTRUDA at
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.
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